title: CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity.
abstract: Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(O)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (P < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.
authors.affiliation: Biological Research Laboratories IV, Daiichi Sankyo Co Ltd, Hiromachi, Shinagawa, Tokyo, Japan. yamashita.makoto.yr@daiichisankyo.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.forename: Takanori
authors.initials: T
authors.lastname: Tomozawa
authors.forename: Masayo
authors.initials: M
authors.lastname: Kakuta
authors.forename: Akane
authors.initials: A
authors.lastname: Tokumitsu
authors.forename: Hatsumi
authors.initials: H
authors.lastname: Nasu
authors.forename: Shuku
authors.initials: S
authors.lastname: Kubo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy*; D051379:Mice; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D053243:Zanamivir / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D009439:Neuraminidase; D053243:Zanamivir